$1.8 Million to Search for New Mood-Disorder Drugs, in Collaboration with Wyeth Research Labs

The National Institute of Mental Health (NIMH) has awarded the School of Medicine $1.8 million over the next three years to establish a National Cooperative Drug Discovery Group for the Treatment of Mood Disorders (NCDDG-MD). This group is comprised of researchers from the Center for Neurobiology at Penn and the Neuroscience Discovery Department at Wyeth Research Laboratories, Princeton, N.J. The aim of this National Institutes of Health (NIH)-sponsored academic-industry collaboration is to develop new antidepressant drug treatments based on the role of neurogenesis (the production of new neurons) in regulating stress and depression.

The Wyeth component is led by Dr. Lee Schechter, who is the Therapeutic Area Head for Depression and Anxiety Research in Neuroscience Discovery. “The previous research findings demonstrating that antidepressants can induce neurogenesis in the brain has opened up a new and exciting area for scientific investigation delving into novel mechanisms of antidepressant drug action,” says Dr. Schechter. “We are very excited about this initiative with Penn under the NCDDG-MD program.”

According to the World Health Organization (WHO), approximately 121 million people currently suffer from depression, which can lead to reduced productivity in the workplace and home. “Depression causes immense financial burdens for individuals and their families, as well as society,” echoes Dr. Lucki. WHO estimates that the annual costs of mental illness in the U.S. is close to $148 billion. Although effective treatments for depression do exist, they are marked by limitations, such as side effects and a three-to-five-week delay before they take effect. And, less than 60 percent of patients seeking treatment respond to current antidepressants.

In recent years, advances in imaging techniques have allowed researchers to scan the brains of patients suffering from depression. Such brain images show distinct shrinkage in the hippocampus and cortex, regions known to play a role in mediating mood and cognitive reasoning. Animal studies reveal that chronic stress leads to similar volume and cell loss in these brain regions, suggesting a link between depression and stress throughout the lifetime.

“Increasingly, we are learning that certain areas of the brain are responsible for generating new cells, and this renewal process is causing us to reexamine the way that stress affects the brain,” explains Dr. Lucki. Stress reduces the amount of neurogenesis, or cell growth, in these areas of renewal. Conversely, chronic administration of antidepressant drugs increases neurogenesis. The NCDDG-MD is in the midst of identifying compounds that facilitate neurogenesis in key areas of the brain to develop innovative therapies for depression.

Recently, Penn and Wyeth researchers examined a hormone called insulin-like growth factor (IGF-1) that has been shown to promote neurogenesis. Dr. Brian Hoshaw, research associate in the Department of Psychiatry at Penn, in collaboration with Dr. Jessica Malberg, senior research scientist in Neuroscience Discovery at Wyeth, discovered that IGF-1 produces behavioral effects similar to antidepressant treatments in animal models. With further examination of the way that IGF-1 and other neurotrophins increase neurogenesis, the research team may be able to develop better antidepressant drugs.

The NCDDG-MD is also developing an animal model capable of detecting the effects of antidepressants on chronic stress using neurogenesis. With such a model, researchers could begin to better understand the delay in drug efficacy of antidepressants and how this may relate to changes in neurogenesis, suggest Dr. Lucki and Dr. Schechter.